2-substituted furan-3,4-dicarboxylic acids, their corresponding saturated analogues and derivatives thereof



Patented Dec. 2, 1947 UNITED STATES PATENT OFFICE Z-SUBSTITUTED FURAN-3,4-DICARBOXYLIC ACIDS, THEIR CORRESPONDING SATU- RATED ANALOGUES AND DERIVATIVES THEREOF Klaus Hoimann, Summit, N. J., asslgnor to Cilia Pharmaceutical Products, Incorporated, Summit, N. J a corporation of New Jersey No Drawing. Application November 24, 1943,

Serial No. 511,610

6 Claims. (Cl. 260-345) 1 2 The present application is in part a continua- This phase of the procedure may be exemplition of copending application, Serial No. 459,674, fled by the following scheme:

filed on September 25, 1942, and the invention to 000R, 3,000 0003,

which the present application relates is a further H a development of the invention described and 5 (CHQFR m claimed in said copending application. \0/ 0 H 0'C"(CH2):"R

A principal object of this invention is the H H preparation of new and useful derivatives of the 2-substituted furan-3,4-dicarboxylic acids of the n In general formula R'0OC\ ooon' R'OOG coon 1 H000 COOH fi- HtJ-O-(J-(CHzh-R nc /C-(CH2)z-R Hi") tv-wnm-n Hi Hi 0 iv v B'ooo coon' H NHNOC CONHNH and of the corresponding tetrahydro-dicarboxylic I acids of the formula H H H H In HO 0 C C 0 0H mi HJI-(CHah-R mo Ho-(cHnr-R 2o C-CH 0 0 Hi0 Hr( Hi)=R o The hydrazides VII may then be converted,

through the intermediate azides VIII, into the with especial reference to those situations wherecorresponding isomeric 3,4 diammocarbethxy i igg i f g i CH2OH group and :6 meme derivatives DI. These may be subjected to hy- A still further object of the invention is to gig-( g 5 211? gz fiia mg glij g gggg f g procedures useful in the prep' be isolated in salt form e g. as the sulfuric acid i analogues 0 salt. This phase of the procedure may be exemccordmg to the present invention, the aforeufiedb the following Scheme.

described furan derivatives may be prepared by p y reacting a Z-substituted furan derivative II with ENHNOO N100 Com an acetylene-dicarboxylic acid ester to produce c -c --s H H e the complex intermediate III, which is then par- 3r tially hydrogenated with the aid of a suitable H R (and catalyst to form the compound IV. The latter, 0 0

on distillation, loses one molecule of ethylene, v11 V111 and forms the corresponding 2-substituted iuran-dicarboxylic ester V which, by catalytic hy- 40 HBCQOOCHN NHCOOCzH HZN drogenation, may be converted into the corre- H H EC |H sponding saturated analogue VI. Treatment of p t: H(J(CHi)=-R EICLI nc-(cnm-n .nisoi the reduction products with hydrazine hydrate results in the production of a mixture of stereoxx x isomeric hydrazides VII.

An important refinement of the invention, par ticularly with respect to this phase thereof, is the step of converting the C'H:OH group at the end of the aliphatic side chain (R in the starting materials representing the primary alcohol group) to a carboxyl group by oxidation, for example with chromic acid in glacial acetic acid, prior to ei'fecting' the hydrolysis from stage IX to stage x, thus:

mciooo cooolm o fl-(crmi-cmon n o [whip-onion II!) V HlCiOOC COOCsHl H-(CHsh-CHzOH HsCsOOCHN NHCOOCIHI n-- H Hid nc-(clmr-coon mN NH:

3- H 6 Hd-(Cfldr-OOOE The transition from 11b to V is through the corresponding stages III and IV, as shown in the first scheme, supra. The transition from VII to IX is through the corresponding 3,4-diazide (VIII).

Suitable starting materials are the z-substituted furans of the general formula II wherein R stands for a carboxyl group or a group, preferably CH2OH, which can be transformed into a carboxyl group, and :1: stands for one of the numbers 2, 3, 4, etc.

Among the groups which can be transformed to a carboXyl group the following ones may be mentioned: aliphatic and aromatic esters such as methyl. ethyl, propyl, phenyl, benzyl esters; aliphatic and aromatic amides such as amide, monoand dimethyl amide, diethyl amide, piperi; dide, anilide, N-methylanilide; nitrile; hydroxyl; halogen; aldehyde and derivatives thereof such as acetal.

Esters of the acetylene-dicarboxylic acid which may be used in the reaction are, for example methyl, ethyl, propyl, isopropyl, phenyl, benzyl esters.

For the partial reduction of the intermediate of the Formula III the following catalysts may for example be used: metals of the platinum group such as platinum, palladium or others as v such or on carriers, or nickel in the various forms production of such substances.

The following examples illustrate methods of carrying out the present invention, butit is to be understood that the examples are given by way of illustration and not of limitation.

Example 1 1.2 g. of furyl-(2)-n-valeric acid ethyl ester were mixed with 980 mg. of acetylene-dicarboxylic acid-diethyl ester and the mixture was heated on the steam bath for 18 hours, after which time the mixture was taken up in 10 cc. of ethyl acetate and was hydrogenated in the presence of palladium black until 1 molecule of hydrogen has been absorbed.

The catalyst was then separated from the solution and the ethyl acetate was evaporated in vacuum, leaving a viscous oil which was distilled in vacuum. The fraction boiling between 165-168 C. at 0.01 mm. pressure was collected and represents the triethyl ester of furan-3,4-dicarboxy- (2) -n-valeric acid. I When the ester is treated with alkali the free tricarboxylic acid is obtained. M. P. 188-189 C.

The tricarboxylic acid was suspended in water and enough 2N KOH was added to make the solution pink to phenolphthalein. Raney nickel was added to the solution audit was hydrogenated at 2400 pounds and 150 C. for 5 hours. The solution was then acidified to Congo red. was evaporated to dryness in vacuo and the organic material was extracted with ethyl acetate. The extracted acids were esterifled in theusual manner and the methyl ester was distilled and the tetrahydro-3,4-dicarb-methoxy-furam (2) -nvaleric acid methyl ester was obtained.

Example 1a 46.7 g. of furyl-(Z) -n-valerlc acid were dissolved in 500 cc. of 4% absolute alcoholic HCl and the solution was kept at room temperature for 12 hours. The solution was then concentrated to a small volume in vacuo and the ester was isolated in the usual manner. The ester was obtained as a colorless liquid which boiled at 130-133 C. at 16 mm.

Example 2a 10 g. of the above ethylester of furyl-(2l-n- 'valeric acid were dissolved in 100 cc. of absolute was removed by steam distillation. The aqueous residue was extracted with ether, the ethereal solution was washed with water, dried over sodium sulfate and the ether was removed on the steambath. Theresldual viscous oil was then distilled in vacuo and yielded Iuryl-(2) -n-pentanol boiling at 125-130 C. at 16 mm.

Example Example 3 A solution of 2.35 g. or fury1-(2) -n-valeric acid piperidide and 1.42 g. of acetylene-dicarboxylic acid-dimethyl ester were boiled for hours in 50 cc. of dry benzene. The benzene was then evaporated in vacuum and the viscous residue dissolved in 20 cc. of methanol and hydrogenated in the presence of Raney nickel catalyst until one molecule of hydrogen had been absorbed. The solution was then separated from the catalyst by filtration, concentrated to dryness and the residue was distilled in vacuum. The distillate was dis solved in a mixture of 5 cc. of methanol and 3 cc. of 5/N aqueous KOH, and the solution was refiuxed for 2 hours. The methanol was removed in vacuo and the residue was acidified to Congo red. The furan 3,4 dicarboxy -(2) n valeric acid piperidide separated out, which melted after recrystallization at 131 C. This material was hydrolized by boiling it 6 hours with 50 cc. of a mixture of 50% glacial acetic acid and 50% concentrated hydrochloric acid. The residue after evaporation of the acetic acid hydrochloric acid mixture melted at 188-189 C. and was identical with the material obtained according to Examples 1 and 2.

4 grams of 3,4 dicarbethoxy furan 2) n valeric acid piperidide were dissolved in 40 cc. of ethyl alcohol and were hydrogenated in the presence of nickel on kieselguhr catalyst at 150 C. and 2500 pounds pressure. The catalyst was then removed by filtration and the 3,4-dicarbethoxytetrahydrofuran 2) n valeric acid piperidide was distilled in vacuum.

Example 4 1.98 g. of furyl-(Z)-n-valeraldehyde-dimethyl acetal were heated in a sealed tube with 1.42 g. of acetylene-dicarboxylic acid-dimethyl ester for 10 hours to 90-100 C. The viscous oil was then dissolved in 20 cc. of ethyl alcohol and was hydrogenated in the presence of platinum black catalyst. The hydrogenation came to an end when the amount of hydrogen, corresponding to one double bond, had been taken up. The solution was then separated from the catalyst and was evaporated in vacuo. The residue was distilled in vacuo to decompose the complex and the distillate was dissolved in a mixture of 20 cc. of methanol and 20 cc. of 5N NaOH and kept at 20". C. for 48 hours. The methanol was then distilled oil and Congo red and heated on the steam bath for 2 hours. The 3,4-dicarboxy-iuryl-(2) -n-valeraldehyde was extracted with ether and was oxidized with freshly prepared silver oxide in alkali solution. The tricarboxylic-acid obtained melted at 188-189" C. and was identical with the substance obtained according to Example 1.

Example 5 1.54 g. of furyl-(2)-n-butyi'ic.acid and 1.70 g. of acetylene-dicarboxylic acid-diethylester were dissolved in 20 c.. of toluene and the solution was refluxed for 5 hours. The toluene was then removed and the residue was hydrogenated in ethylalcohol solution in the presence of palladium on barium-sulfate catalyst. The catalyst was then removed and the alcohol was evaporated in vacuo. The residue was distilled in vacuo, whereby the addition compound was decomposed and 3,4-dicarbethoxy-furan-(2)-n-butyricacid was obtained. Saponification of the ester yielded 3,4-dicarboxy-furan-(2) -n-butyric acid.

Example 6 A mixture of 30.8 g. of furyl-(2)-n-pentanol and 37.6 g. of diethyl acetylene dicarboxylate were heated on the steam bath for 6 hours and the resulting viscous addition compound was dissolved in 200 cc. of ethyl acetate and was hydrogenated in the presence of a palladium catalyst until 5.7 liters of hydrogen had been absorbed. The catalyst was removed by filtration and the partially hydrogenated material was decomposed into ethylene and 3,4-dicarbethoxy-furan-(2)- n-pentanol which was purified by distillation. B. P. I'M-175 C. at 0.01 mm.

Example 7 1.5 g. of the above 3,4-dicarbethoxy-furan-(2) n-pentanol were refluxed for 2 hours with 4 cc. of 5NKOH and 8 cc. of methanol. The solution was then concentrated to a small volume in vacuo and acidified to Congo red with concentrated HCl. The resultant crude 3,4-dicarboxyfuran-(Z) -n-pentanol was purified by crystallization from ethyl acetate and melted at 124- 126 C.

Example 8 1 g. of the above 3,4-dicarboxy-furan-(2)-npentanol was dissolved in 10 cc. of glacial acetic acid, and 42 cc. of a 2% solution of chromic acid in glacial acetic acid were slowly added. The solution was kept at room temperature for 12 hours and the excess of chromic acid was destroyed by the addition of 5 cc. of methanol. The solvents were removed in vacuo and the dark green residue was dissolved in water and extracted with ethyl acetate. Theethyl acetate extracts-were washed with water, dried over sodium sulfate and concentrated to a small volume on the steam bath. 3,4-dicarboXy-furan- (2) -n-valeric acid melting at 188-190" C. identical with the substance described in Example 1 was obtained.

Example 9 31 g. of 3,4-dicarbethoxy-furan-(2)-n-valeric acid ethyl ester were dissolved in cc. of grain alcohol and were hydrogenated in a. steel bomb in the presence of a nickel-on-kieselguhr catalyst at an initial pressure of 1900 pounds and a temperature of -180 C. for 3 hours. The catalyst was removed by filtration and the alcohol was removed in vacuo. The oily residue was dissolved in ether, was washed with 2N sodium carbonate and water and dried over sodium sulfate.

i ,the residue was distilledlin vacuo.

The ether was removed on the steam bath and The hydrogenated esters boiled at 162-168" C. at 0.01 mm. and hadthe following constants:

d=1.094- n =1.-i5'l9 Example g. of 3,4-'dicarbethoxy-furan-(2)-n-pentanol were dissolved in 200 cc. of grain alcohol and were hydrogenated in the presence of a Raney nickel catalyst at an initial pressure of 1900 pounds and a temperature of I'm-180 C. for 3 hours. The hydrogenated esters were isolated as described in Example 9 and-they had the following constant;

Example 11 Example 1.2

500 mg. of the above hydrazide A were dissolved in 10 cc. of 1N hydrochloric acid and the solution was cooled to 0 C. 3 cc. of a 10% solution' of sodium nitrite were slowly added with vigorous stirring and stirring was continued for an additional 10 minutes. The azide was extracted with ice-cold ether and the ether extracts were washed with 10% sodium-hydrogen carbonate and water, and dried over sodium sulfate. 20 ccLof absolute ethanol were then added, the

ether was removed and the residual alcoholic solution was refluxed for 1 hour. The alcohol was removed and a crystalline 3,4-diaminocarbethoxytetrahydrofuran -(2)-n-pentanol was obtained. Degradation of the isomeric hydrazides B and C resulted in the formation of two additional isomeric 3,4-cliaminocarbethoxytetrahydrofuran- (2) -n-pentanols Example 13 Each of the three isomeric urethanes described above was oxidized as follows: 477 mg. of the material were dissolved in 5 cc. of glacial acetic acid and 14.4 cc. of a 2% solution of chromic acid in glacial acetic acid were slowly added. The solution was kept at room temperature for 12 hours and the excess of chromic acid was destroyed by the addition of 2 cc. of methanol. The solution was evaporated to. dryness in vacuo and the dark tracted with ethyl acetate. The ethyl acetatesoluble parts were separated into acid and neutral substances with 2N sodium carbonate in the usual manner. From the respective acid fractions three isomeric 3,4-diaminocarbethoxytetrahydroiuran-(2) -n-valeric acids were obtained.

Example 14 The above three isomeric 3,4-diaminocarbethoxytetrahydrofuran-( 2) -n-valeric acids were hydrolyzed as follows: 213 mg. of the respective urethane were heated to 110 C. in a sealed tube with 1.2 g. of Ba(OH) 2.81110 and 10 cc. of water for three hours. The excess of baryta was then removed with CO: and the barium carbonate was filtered off. The clear filtrate was acidified to Congored with 10% sulfuric acid, the precipitate of barium sulfate was' removed and the filtrate was concentrated to a small volume in, vacuo.

Addition of methanol resulted in the precipitation of the respective 3,4-diaminotetrahydrofuran- (2) -n-valeric acid sulfate.

Iclaim:

1. The 2-substituted furan 3,4-diamino compounds of the formula HzN x-(cnom wherein X is a nucleus of the group consisting of the furan and tetrahydrofuran nuclei, the NH: groups being attached in the 3,4-positions of the said nucleus and the (CH2)R group being atgreen residue was dissolved in water and was extached in the 2-positi0n-of the said nucleus, a: being one of the integers 2, 3, and 4, R being a member of the group consisting of carboxyl and a group convertible to carboxyl.

2. The Z-substituted furan compounds of the formula mN NH:

Loy (CHAIR wherein R is a member of the group consisting of carboxyl and a group convertible to carboxyl, and a: representing one of the integers 2, 3, and 4.

3. The 2-substituted tetrahydrofuran compounds of the formula wherein R is a member of the group consisting of carboxyland a group convertible to carboxyl, and :0 representing one of the integers 2, 3 and 4.

4, A 3,4-diaminotetrahydrofuran-(2) -n-valeric acid of'the formula Hm NH:

IE H mo gel-(01101420011 5. In a process for the manufacture of a biotin analogue, the steps of subjecting a compound of the formula wherein Y is a group which is hydrolyzable to amino and a: is one of the integers 2, 3 and 4, to oxidation to convert the primary alcohol group to a carboxyl group, and then subjecting the resultant product to hydrolysis.

6. In a process for the manufacture of a biotin ing 3,4 diamino tetrahydrofuran-(2) -n-va1eric analogue, the steps of subjecting a urethane or acid. the formula KLAUS HOFMANN.

HiCzOOCHN Nncooonzh H 5 REFERENCES CITED The following references are of record in the mxnJJ-(cmh-cmon me of this patent:

UNITED STATES PATENTS to oxidation by means of chromic acid in glacial acetic acid to produce the corresponding urethane m Number Name Date of tetrahydrofuran-(2) -n-va1eric acid, and then 2905538 Engelmann June 18, 1935 subjecting the latter to hydrolysis with the aid 2331.78! Adams et a1 11,1941

of barium hydroxide to produce the correspond- 2,317,236 M in et a1 Apr. 20, 1943 

